Cyclization process



United States Patent 2,775,603 CYCLIZATIION PROCESS John C.SheehamArlington, Mass.

No Drawing. Application October 2, 1953,

SerlalNo.383,914 H s c 1} zoo-391.4

O 02 OH:

-OH: 010E:

Preferential saponiflcatlon 1" CH|O Arndt-Elstert OHO The acyloincondensation would offer advantage in carrying out ring formations ofthe above type, particularly in that it would avoid the essentiallywasteful homologation steps and the loss of carbon atoms in closing thering.

For the most part the acyloin condensation has been carried out inheterogeneous media, suspending finely divided sodium in solvents suchas xylene, toluene, and the like. Diesters susch as ,diethyl pimelatehave been cyclized using a ratio of 4 atoms of sodium to one mole ofdiester. Vigorous stirring and an inert atmosphere are also required.Very good yields are obtained in the preparation of relatively largealiphatic rings using ordinary, procedures. However, with smaller rings,and especially where the diester contains bulky components "such as arylgroups, special care such as high-dilution addition of the diester overa long period of time is mandatory. Even then only a low yield ofacyloin is obtained.

Recently it has beenfound that the acyloin condensation can be carriedout in homogeneous media. adipate has been cyclized to a six-memberedacyloin using sodium in homogeneous liquid ammonia solution.

It has now been found that the acyloin condensation may be carriedout inhomogeneous media to effect the closure of the'A, B, C and D rings(designated in 11.

below) in the synthesis of steroids such as estrone (H),

F ,iCe ,775,603

fl atented Dec. 25, 1956 equilenin (III), estradiol (IV), estriol '(V),and the like. For example, dimethyl marrianolate OH: CH8

11 I OH: on,

on on nono QO:OH:

-oniomooioni moons om. V

COICH:

CHI

By contrast, when the dimethyl marrianolate methyl ether was treatedwith an excess of sodium in a reaction medium of. 60% liquid ammonia and40% anhydrous HaGChO v ether, adding :the diester in either solutionduring one hour, the reaction was very rapid, the rate of diester HaCOnC002E COzH VIII

The diester (VII) is obtained by the nitric acid oxidation ofl2-hydroxycholanic acid or by the chromic acid oxidation of an11,12-acy1oin mixture to 11, 12-seco-cholane- 11, 12, 24-triacid (Z.Physiol. Chem. 110, 141 (1920-);

V Helv. Chim. Acta. 25, 816 (1942)) followe'diby esterification withdiazomethane and selective saponification.

The cyclization of the aforementioned dimethylmarrianolate methyl etherillustrates v.the use of the present invention in the formation of the Dring of the steroids. Another example of closing the D ring using thepresent invention is the cyclization of dimethyl aetioallobilianate (IX)via the acyloin reaction to provide the u-ketol The diester IX isavailable by the total synthetic route (J. Chem. Soc. 361 (1953)) or byhydrogenation and esterification of 3/3-hydroxyaetiobilienic acid, abyproduct of the oxidation of cholesteryl acetate dibromide (J.

'Pharm. Soc.IJapan 65, 631 (1936)).

Examples of the applicability vof the acyloin reaction in homogeneousmedia to the formationof the A and B rings of the steroid nucleusfollow:

Dimethyl cholestan-Z, 3-seco-dicarboxylate (XI) obtained by chromic acidoxidation of cholestanol (Ber. 47, 2384 (1914)) may be cyclized to thea-ketol XII.

HaOOzC BIO a a I X11 Dimethyl cholestan-B, i-secodioarboxylate (XIII)described in Helv. \Chim. Acta. v 25, 1434 1942) and prepared fromcholestanone'by pei'benzo'ic acid oxidation, hydrolysis of the resultantlaetone, esterification of the carboxyl group, oxidation of thehydroxyester to a half t ster ,followed by comp te teste ifiq t anmay hey li to the a-ketol XIV The dimethyl ester of 3-hydroxycholastan-6,7-seco dicarboxylic acid (XV), prepared by esterification of thecorresponding diacid obtained (Ber. 37, 3699 (1904)) by the nitric acidoxidation of 6-ketocholesteryl chloride followed by hydrolysis of the3-chloro substituent may be cyclizedtothe'a-ketol allowed to come slowlyto room temperature.

A detailed example of the manner in which the process of the presentinvention may be employed to efiect ring closures in the preparation ofsteroids is set forth below:

l6-keto-17fiestradiol-3-methyl ether (II ).To a 1 l. three-necked flaskfitted with a Dry Ice condenser, stirrer, addition funnel, and nitrogensystem was added 200 m1. of dry ether and 300 ml. of anhydrous liquidammonia. In this liquid was dissolved 0.80 g. (0.02348 g.-atom) offreshly-cut sodium. The system was swept thoroughly with prepurifiednitrogen and all subsequent operations up to the extractions werecarried out under a slow stream of nitrogen. A solution of 1.82 g.(0.005 mole) of dimethyl marrianolate methyl ether in 180 ml. of dryether was added during 1 /2 hours with efficient stirring, and thestirring was continued as the flask was After 4 hours only a trace ofammonia could be detected in the exit gases. To the white suspension ofexcess sodium and sodium enolate of acyloin in ether was added 2 ml. ofmethanol in 100 ml. ether (to destroy excess sodium) and the mixture wasacidified with 50ml. of 5% hydrochloric acid. After partition andseparation, the aqueous layer was extracted with an ether-methylenechloride mixture, and the combined organic solution was washed withdilute sodium bicarbonate and water. Removal of the solvents underreduced pressure afiorded 1.44 g. (96%) of colorless crystallineproduct, M. P. 163l66; [a] =-85 (0:1 in ethanol). Treatment withcharcoal and recrystallization from aqueous acetone gave silky needlesof 16-keto-17fi-estradiol-3-methyl ether (VI), M. P. 169.5-171"; [a] =87(0:1 in ethanol). 1

Anal.-Calcd. for C19H24O2: Found: C, 75.79; H, 8.09.

Upon admixture with a sample of 16-keto-17B-estradiol-3-methy1 ether, M.P. 169170.5; [a] =88 (c=1 in ethanol), prepared from 16-oximinoestronemethyl ether according to the method of Butenandt (Z. Naturforchung 1,82 (1946)), the M. P. was 169-170.5 (undepressed) A sample of VIprepared by the acyloin cyclization was converted to an oximederivative. After three recrystallizations from ethanol the M. P. (dec.,in bath at 194) was 199.5-200".

Anal.Calcd. for C19H25O3N: C, 72.35; H, 8.00. Found: C, 72:39; H, 8.21.

Generally, in carrying out the reaction 4 atoms of sodium are employedfor each mole of the diester which is condensed. Excess sodium may beemployed if desiredand in many cases is beneficial. In addition tosodium it is also possible to employ other alkali metals such aspotassium, although from a practical standpoint sodium is preferredbecause of its greater availability,

cost and ease of handling.

' Other solvents besides liquid ammonia may be employed to dissolve thealkali metal such as sodium or potassium, such other solvents beinganhydrous methylamine and anhydrous hydrazine. Other solvents for theseco-steroid diester which may be employed instead of ether as mentionedabove include tetrahydrofuran and the dimethyl ether of ethylene glycol.

Experiments indicate that the temperatures at which the reaction may becarried out are not critical. Generally, it is preferred to carry outthe reaction at near room temperatures. In the case where liquid ammoniais used it is most convenient to carry out the reaction at a temperatureof about 35 C., the boiling point of the ammonia. Where the ammonia isreplaced by anhydrous methylamine as a solvent for the alkali metal thetemperature more conveniently employed is of the order of l0 C. Highertemperatures may be employed with anhydrous hydrazine as the solvent forthe alkali metal.

It will be understood that the details set forth above are by way ofexample only and that various procedural modifications within the spiritof the invention will occur to those skilled in the art.Accordingly,,reference should be had to the appended claims for adefinition of the limits of the present invention.

What is claimed is:

1. In the acyloin condensation of a seco-steroid diester to form asteroid ring, the improvement comprising carrying out said cyclizationwith sodium in a homogeneous medium.

2. In the acyloin condensation of a seco-steroid diester to form asteroid ring, the improvement comprising carrying out said cyclizationwith sodium dissolved in liquid ammonia.

3. In the acyloin condensation of a seco-steroid diester to form asteroid ring, the improvement comprising carrying out said cyclizationwith sodium dissolved in liquid ammonia and diethyl ether.

4. The process of producing l6-keto-l7fl-estradiol-3- methyl ether whichcomprises eifecting the acyloin condensation of dirnethyl marrianolatemethyl ether with sodium in liquid ammonia and diethyl ether.

5. In the acyloin condensation of a seco-steroid diester to form asteroid ring, the improvement comprising carrying out said cyclizationwith alkali metal in a homogeneous medium.

References Cited in the file of this patent UNITED STATES PATENTS514,516 Great Britain Nov. 10, 1939

1. IN THE ACYLION CONDENSATION OF A SECO-STEROID DIESTER TO FORM ASTEROID RING, THE IMPROVEMENT COMPRISING CARRYING OUT SAID CYCLIZATIONWITH SODIUM IN A HOMOGENEOUS MEDIUM.